Atomic force microscopy and MD simulations reveal pore-like structures of all-d-enantiomer of Alzheimer's β-amyloid peptide: Relevance to the ion channel mechanism of AD pathology

Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; l-amino acid peptides, but not their d-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like l-amino acids, d-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both d- and l-enantiomers of the full length Aβ _1-42 when reconstituted in lipid bilayers. AFM imaging shows that both l- and d-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that d-Aβ_1-42 channels conduct ions similarly to their l- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors.